SUMMARY Personalized medicine, based on the genomic context of a patient?s disease, has become a leading strategy to treat cancer. However, despite the promising results from customized treatments, targeted therapies affect the same signaling pathways in non-cancerous cells, often leading to dose-limiting, ?on-target? toxicities. One such example involves PI3K inhibitors. In head and neck squamous cell carcinoma (HNSCC), the 6th most common cancer worldwide, 34%-56% of tumors harbor mutations or amplifications in PIK3CA, the gene coding for the p110? subunit of PI3K. PI3K? inhibitors carry a significant toxicity profile, however, that limits their therapeutic window, specifically in patients who develop intractable hyperglycemia. Using a targeted drug delivery approach, we have identified a strategy to address this need. The PI developed a new class of nanoparticles targeted to P-selectin which allows the incorporation of a wide variety of therapeutic molecules, including targeted therapies (Shamay, Sci Transl Med 2016). We built a collaborative research team that employed this technology to target tumors expressing endothelial P-selectin, either at baseline or radiation-induced (Mizrachi, Nat Commun 2017). The strategy effected a significantly improved therapeutic index and survival, while minimizing the side effects of targeted therapeutics. Notably, we found that PI3K inhibitors, targeted using our nanoparticle vehicle, resulted in prolonged pS6 inhibition and anti-tumor efficacy, while minimizing acute and chronic effects of hyperglycemia. The objective of this project is to investigate, in the context of HNSCC, the nanoparticle-mediated delivery of PI3K therapies via P-selectin, expressed spontaneously or induced by radiation. This proposal?s goals are to understand the modulation of drug pharmacology, efficacy, toxicities, interactions with HNSCC tumor microenvironment, and the impact of ionizing radiation on these parameters. We plan to pursue the following specific aims: 1) Assess P-selectin-mediated targeting to the tumor microenvironment. We will measure the localization of the nanoparticle and encapsulated drug in the tumor microenvironment from the organ to cellular levels. 2) Enhance nanoparticle localization via radiation-induced endothelial activation. Based on our understanding of radiation-induced expression of P-selectin, we hypothesize that external beam radiation can increase localization of a P-selectin-targeted PI3K inhibitor in disseminated tumors due to the increased availability of the target. 3) Assess efficacy of P-selectin-mediated targeting of PI3K inhibitors. We will assess the relationship between drug delivery mechanism and treatment response. We hypothesize: (i) that the P-selectin-based targeting will improve PI3K inhibitor-mediated efficacy and apoptosis in tumors, (ii) that radiation may increase the relative efficacy of the inhibitor, (iii) that nanoparticle-mediated P-selectin targeting will mitigate PI3K-mediated hyperglycemia, and (iv) that nanoparticle-delivered therapeutic combinations will improve synergistic effects while attenuating toxicities that arise from systemic administration of multiple inhibitors. The outcomes will inform IND and clinical studies.